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THE ROLE OF APOPTOSIS IN NEUROTOXICOLOGY.
Citation:
Barone, S, M. Ehrich, AND L. D. White. THE ROLE OF APOPTOSIS IN NEUROTOXICOLOGY. Presented at Society of Toxicology, San Franscisco, CA, March 25-29, 2001.
Description:
The role of apoptosis in neurodegeneration in developing animals and in adults has become increasingly apparent in the past ten years. Normal apoptosis occurs in the CNS from the embryonic stage through senescence, with different cells in each region of the nervous system having characteristic temporal patterns of programmed cell death. Several different stimuli trigger the apoptotic cascade and its different intracellular signaling pathways. For example, mitochondrial calcium overload, reactive oxygen species, and the alteration in neurotrophic factor signaling. This receptor-mediated signaling is achieved though the interaction of p75NTR and trkA receptors to modulate apoptotic cell death in developing and adult neural tissues. Both in vivo and in vitro experiments have implicated that exposure to a number of neurotoxicants results in apoptosis. Exposure of organogenesis-stage mouse embryos to hydroxyurea, chemotheraputic drug, or disinfection by-products results in increased apoptosis during neurulation. Ethanol, a widely used neurotoxicant, has been shown to affect apoptosis, as well as proliferation and migration, in developing animals. Two environmental contaminants, mercury and lead, have both been implicated in apoptotic cell death. Lead exposure to developing or adult neural cells produces apoptosis by opening the mitochondrial permeability transition pore and activating the calcium-dependent cytochrome c-caspase cascade. In vivo methylmercury exposure produces apoptosis in cerebellum, and studies of apoptosis in vitro with PC12 cells suggest involvement of a neurotrophic factor-dependent mechanism. Organophosphate exposure targets mitochondrial function by altering membrane potential and substrate adhesion, resulting in apoptosis. Thus, a variety of neurotoxicants modulate or produce apoptosis through alterations in developmental processes or alterations in cellular and subcellular homeostasis. This symposium will present current research in this area and will illustrate how alterations in apoptosis result in morphological or functional deficits in the nervous system. (This abstract does not reflect USEPA policy).